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PubMed1998

Molecular detection of genetic alterations in the serum of colorectal cancer patients.

We have searched for the presence of genetic alterations in serum DNA obtained from 44 colorectal cancer patients. Microsatellite analysis using highly polymorphic markers revealed loss of heterozygosity and/or microsatellite instability in 35 of 44 (80%) primary tumors. No alterations were detected in the paired serum DNA. We next used an oligonucleotide-mediated mismatch ligation assay to detect tumor specific gene mutations in the serum. Among the 16 cases with a K-ras gene mutation in the tumor, the same mutation was detected in three paired serum samples. In the 10 cases with a p53 mutation in the tumor, the identical mutation was detected in seven corresponding serum samples. Comparison of the molecular analysis with clinical diagnosis of these patients revealed that none of the seven Dukes' stage B patients with a K-ras mutation in their tumors demonstrated a mutation in the serum. In contrast, five of seven stage B patients with a p53 mutation in the tumor demonstrated a mutation in the paired serum (P = 0.01, Fisher's exact test). Taken together, either a K-ras or p53 mutation was detected in the serum in 40% of the 25 patients (95% confidence interval, 21-61%), whose primary tumors contained a mutation and in 23% of the 44 patients (95% confidence interval, 12-38%) with colorectal cancer. The frequent detection of p53 mutation in the serum of patients with early stage tumors suggests a possible use of this approach for clinical prognosis and cancer monitoring of colorectal cancer patients.

Alleles↗

PubMed1996

Frequent microsatellite instability in post hepatitis B viral cirrhosis.

The molecular basis of cirrhosis, the most frequent underlying liver disease in hepatocellular carcinoma, remains unclear. We investigated microsatellite instability at six different loci on chromosomes 2p, 3p, 5q, 9p, 13q and 17p, in DNA from 38 cirrhotic livers of viral (n=28) and nonviral (n=10) origin. Sixty percent of the patients exhibited microsatellite alterations in at least one chromosome locus. A striking feature was the close association between genomic instability and cirrhosis linked to hepatitis B viral infection (P<0.01). This high instability may be a clue to the etiology of cancer induced by the hepatitis B virus.

Adult↗

PubMed2005

Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.

BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs. METHODS: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene. RESULTS: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene. CONCLUSIONS: PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Frequency of the Amsterdam criteria in a regional German cohort of patients with colorectal cancer.

Estimates of the colon cancer burden associated with hereditary nonpolyposis colorectal cancer (HNPCC) vary from less than 1 % to more than 5 %. Amsterdam criteria fulfilled within a kindred (classic Amsterdam and Amsterdam II criteria) are widely used to identify patients prone to HNPCC. The present study was initiated to assess the frequency of the Amsterdam criteria within a regional German cohort of 207 patients with a history of colorectal cancer (CRC). Data on individual and family cancer histories were available in 154 patients (73 women, 81 men; mean age at diagnosis 62.4 +/- 13.3 years). A total of 843 first degree relatives have been identified within the kindreds of whom 121 had verified cancers. In 28 of 154 families (18 %), at least one first degree relative of the index patient had CRC. With respect to a typical family history, five kindreds (3.2 %) were likely to suffer from HNPCC on a clinical basis (4 kindreds met the classic Amsterdam criteria and one kindred the Amsterdam II criteria). Testing for microsatellite instability could additionally be performed in 4 of 5 patients who met the Amsterdam criteria and revealed DNA instability in 3 cases. Moreover, a missense mutation of MSH2 (Gly965Asp) was detected in one patient with microsatellite instability. Based on the classic Amsterdam and Amsterdam II criteria approximately 3 % of a regional German cohort of patients with CRC are likely to suffer from HNPCC. However, the final diagnosis of HNPCC can only be established by detection of pathogenic germline mutations within the DNA mismatch repair genes.

Adult↗

PubMed1999

Colorectal cancer with and without microsatellite instability involves different genes.

There is evidence supporting a multistep genetic model for colorectal tumorigenesis. In familial adenomatosis polyposis (FAP), the inherited defect is a mutation in the APC gene. The vast majority of all sporadic colorectal cancers also show mutations in the APC gene, and the tumorigenesis in sporadic colorectal cancer and FAP is assumed to involve the same genes. Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in DNA mismatch repair genes and, as a result of defective mismatch repair, microsatellite instability (MSI) is frequently seen. Tumorigenesis in HNPCC was first thought to involve mutations in the same genes as in FAP and sporadic colorectal cancer. Recently, however, an alternative pathway to development of colorectal cancer has been suggested in colorectal tumors with MSI, compared to those tumors without the MSI phenotype. We used a consecutive series of 191 sporadic colorectal cancers to find out if there were any differences between the two groups of tumors regarding the prevalence of mutations in the APC, KRAS, TP53, and TGFbetaR2 genes. As expected, 86% (19/22) of MSI-positive tumors showed a mutation in TGFbetaR2, while only one of 164 (0.6%) MSI-negative tumors did. A highly statistically significant negative association was found between MSI and alterations in APC and TP53. The MSI-positive tumors were screened for mutations in exon 3 of beta-catenin, which has been suggested to substitute for the APC mutation in the genesis of colorectal cancer, without finding mutations in any of the 22 MSI-positive tumors. The number of mutations found in KRAS was lower in MSI-positive than in MSI-negative tumors but the difference was not statistically significant. Our results strongly support the idea that carcinogenesis in MSI-positive and MSI-negative colorectal cancer develops through different pathways.

Adenomatous Polyposis Coli↗

PubMed2003

Sensitivity and specificity of a stool DNA multitarget assay panel for the detection of advanced colorectal neoplasia.

Colorectal cancer is the second-leading cause of cancer death. New noninvasive options for screening capable of diagnosing cancer at an early stage are needed to improve compliance and reduce mortality. This study was designed to provide an estimate of the sensitivity and specificity of a multitarget assay panel (MTAP) of stool DNA changes. Eighty patients with advanced colorectal neoplasia and 212 control subjects provided stool samples before colonoscopy. Patients with hereditary colorectal cancer syndromes were excluded. The MTAP included 21 specific mutations in the adenomatous polyposis coli (APC), p53, and K-ras genes, a microsatellite instability marker (BAT-26), and a marker of abnormal apoptosis (DNA Integrity Assay). All samples were analyzed in the clinical laboratory at EXACT Sciences. Multitarget assay panel detected 33 of 52 patients (63.5%, 95% confidence interval [CI], 49.0%-76.4%) with invasive colorectal cancer, including 26 of 36 (72.2%) with node-negative disease (American Joint Committee on Cancer [AJCC] stage I/II) and 7 of 16 (43.7%) with advanced disease (AJCC stage III/IV). Sixteen of 28 patients (57.1%; 95% CI, 37.2%-75.5%) with advanced adenomas (lesions containing high-grade dysplasia, villous adenomas, or tubular adenomas > 1 cm in size) were detected, including 6 of 7 (85.7%) with high-grade dysplasia and 10 of 21 (47.6%) with other advanced adenomas. Specificity was 96.2% (95% CI, 92.7%-98.4%) in patients with either no colorectal lesions or diminutive polyps. Multitarget assay panel has better sensitivity than that reported with use of Hemoccult(R) II in fecal occult blood testing, with similar specificity. Sensitivity appeared to be equally high for patients with node-negative and advanced disease, as well as for advanced adenomas. This study contained a disproportionately high number of distal cancers and, as such, may not be representative of results in proximal lesions. Although a prospective study in an average-risk population is needed to validate these findings, MTAP may offer an important noninvasive option for population-based screening.

Adult↗

PubMed1997

Precise assessment of microsatellite instability using high resolution fluorescent microsatellite analysis.

The instability of microsatellite sequences dispersed in the genome has been linked to a deficiency in cellular mismatch repair. This phenotype has been frequently observed in various human neoplasms and is regarded as a major factor in tumorigenesis. To demonstrate alterations in microsatellite sequences, polymerase chain reaction (PCR) and electrophoretic analysis are techniques often used. However, the electrophoretic profiles of PCR-amplified microsatellite sequences have not been well characterized. Moreover, the conventional method using autoradiography has critical problems in detection characteristics and migration accuracy. We made use of fluorescence-labeled PCR and laser scanning with linear detection characteristics, so as to detect bands quantitatively. Next, we characterized Taq polymerase-dependent modification of the amplified microsatellite sequences, using artificially synthesized microsatellite alleles and we optimized the electrophoretic profiles by enzymatic modification with T4 DNA polymerase. We developed a dual fluorescence co-electrophoresis system, in which both samples derived from cancer and normal tissues are electrophoresed in the same lane, in order to minimize migration errors. These improvements remarkably facilitate precise and objective assessments of microsatellite instability. Analyzing many positive cases in cell lines and tissue specimens, we classified all the patterns of microsatellite alteration and set up new criteria for assessing microsatellite instability.

Adenocarcinoma↗

PubMed2004

Aetiology of colorectal cancer and relevance of monogenic inheritance.

BACKGROUND AND AIMS: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. PATIENTS AND METHODS: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. RESULTS: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. CONCLUSIONS: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Reduced COX-2 protein in colorectal cancer with defective mismatch repair.

Most colorectal adenomas and carcinomas arise in the setting of chromosomal instability characterized by progressive loss of heterozygosity. In contrast, approximately 15-20% of colorectal neoplasms arise through a distinct genetic pathway characterized by microsatellite instability (MSI) associated with frequent loss of expression of one of the DNA mismatch repair enzymes, most often hMLH1 or hMSH2. These distinct genetic pathways are reflected by differences in tumor histopathology, distribution in the colon, prognosis, and dwell time required for progression from adenoma to carcinoma. To determine whether these two groups of tumors differ in their expression of cyclooxygenase-2 (COX-2), a putative chemopreventative target, immunostaining for this protein was performed in colorectal cancers categorized by the presence (n = 41) and absence (n = 66) of defective mismatch repair. Defective mismatch repair was defined by the presence of tumor microsatellite instability (MSI-H, > or =40% of markers demonstrating instability) and by the absence of protein expression for either hMLH1 or hMSH2. Overall, our results showed that low or absent COX-2 staining was significantly more common among tumors with defective mismatch repair (P = 0.001). Other features predictive of low COX-2 staining included marked tumor infiltrating lymphocytosis, and solid/cribiform or signet ring histological patterns. These observations indicate that colorectal cancers with molecular and phenotypic characteristics of defective DNA mismatch repair express lower levels of COX-2. The clinical implications of this biological distinction remain unknown but should be considered when assessing the efficacy of COX-2 inhibitors for chemoprevention in patients whose tumors may arise in the setting of defective DNA mismatch repair.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Microsatellite instability in uterine sarcomas.

Studies have shown a 15-30% frequency of microsatellite instability in endometrial cancer. In addition, we found a 21% frequency of microsatellite instability in endometrial cancer. Our aim was to investigate the presence of microsatellite instability and loss of heterozygosity in uterine sarcomas. The records of 69 women referred to Kalafong Academic and Pretoria Academic Hospital with a primary diagnosis of uterine sarcoma were reviewed. At histological review of 43 cases with a primary diagnosis of leiomyosarcoma, diagnosis of mitotically active leiomyoma was made in 21. Diagnosis of carcinosarcoma was made in 21 cases and endometrial stromal sarcoma in five. In all cases, genomic DNA was extracted from normal myometrium and tumor and analyzed for microsatellite instability and loss of heterozygosity. High-frequency microsatellite instability was absent in leiomyosarcoma, endometrial stromal sarcoma, and mitotically active leiomyomas and was observed in 1 (5%) carcinosarcoma. Loss of heterozygosity for chromosome 11 was present in 8/48 (17%) of uterine sarcomas, equally distributed between leiomyosarcomas (4/22 = 18%) and carcinosarcomas (4/21 = 19%). There was no loss of alleles in endometrial stromal sarcoma nor mitotically active leiomyomas. In conclusion, it is suggested that tumor suppressor genes may play a role in the tumorigenesis of uterine mesenchymal cells, whereas mismatch repair genes contribute to the carcinogenesis of endometrial cancer.

Carcinosarcoma↗

PubMed1996

Genomic instability in ovarian cancer: a reassessment using an arbitrarily primed polymerase chain reaction.

Traditional polymerase chain reaction (PCR) amplification of multiple microsatellite markers to detect microsatellite instability (MI) is labor intensive and may be marker dependent. An arbitrarily primed polymerase chain reaction (AP-PCR) is a modification of PCR that generates a genomic DNA fingerprint using a single, arbitrarily chosen primer which is useful in the detection of somatic genetic alterations. We hypothesize that AP-PCR of an AluI DNA restriction digest, which we term Alu/AP-PCR, identifies genomic instability as well. In order to test this hypothesis, we correlated Alu/AP-PCR fingerprints with analyses of traditional PCR amplified microsatellite markers using paired germline and tumor DNA samples obtained from 68 patients with ovarian cancer. The microsatellite markers tested included dinucleotide, trinucleotide, and tetranucleotide repeats. We found that MI is more common in ovarian cancer than previously thought. We estimate a minimum incidence of MI at 37% based on the 10 traditional markers we tested, to an incidence of 53% based upon our Alu/AP-PCR analysis. All cases of MI were associated with an abnormal Alu/AP-PCR banding pattern. Both MI, detected by polymorphic markers (P=0.03), and an abnormal Alu/AP-PCR pattern (P=0.01) were significantly associated with the occurrence of a second primary malignancy in the same patient. In addition, abnormal Alu/AP-PCR patterns were associated with higher grade lesions (P=0.02), and family history of cancer (P=0.009). These findings suggest: (1) MI may play an important role in ovarian carcinogenesis, and (2) Alu/AP-PCR is a novel technique for identification of genomic instability.

Adult↗

PubMed1996

Evidence for genomic instability in human colonic aberrant crypt foci.

Aberrant crypt foci (ACF) are morphologically abnormal structures that can be identified in whole amounts of colonic tissue from rodents treated with colon carcinogens and from patients at risk for development of colon tumors. ACF are heterogeneous and exhibit properties, such as altered patterns of cell proliferation, the presence of dysplasia, and mutations in protooncogenes and tumor formation. In this study, we have investigated the presence of genomic instability in DNA isolated from human ACF from patients with colon cancer. Altered allele length detected by electrophoretic separation of PCR amplified oligo A or microsatellite loci was used to identify candidate samples which were then more rigorously investigated by sequence analysis for instability. Of 20 patients examined, two exhibited alterations at two loci, and this instability could be confirmed by sequence analysis. An additional seven of the 20 patients had evidence for instability at a single locus. Quantitative sequence analysis of the DNA from an ACF of one of these seven patients was consistent with alteration of allele length in this patient, but the alteration was not sufficiently different from normal to reach statistical significance. Thus, genomic instability, manifest as altered length of microsatellite and oligo A sequences, in present in some ACF, and therefore can be a very early event in the development of some human colon cancers.

Adult↗

PubMed2000

Microsatellite instability is not a defining genetic feature of acute myeloid leukemogenesis in adults: results of a retrospective study of 132 patients and review of the literature.

The frequency of acute leukemia in children with constitutional DNA repair defects implicates defective DNA repair in leukemogenesis. Whether sporadic cases of AML also arise from an inherited genetic predisposition remains to be determined. Prior studies have reported microsatellite instability (MSI) in AML, particularly secondary and relapsed AML. These studies included small numbers of cases in which key features such as cytogenetic abnormalities were not reported. To determine whether defective DNA mismatch repair, reflected by MSI, is a defining feature of adult myeloid leukemogenesis, we retrospectively studied 132 AML cases including 28 de novo, 62 secondary, 22 relapsed/refractory, 15 cases of paired diagnosis/relapse. 110 patients were elderly (55+ years). The cases included a range of cytogenetic abnormalities. MSI was assessed at three loci (BAT 25, BAT 26, BAT 40) in DNA isolated from sorted leukemic blasts and paired T cell controls. Fluoresceinated PCR products were analyzed using an automated capillary electrophoresis system. Of the 132 AML cases, no single case demonstrated MSI. Our studies indicate that MSI, and defective DNA mismatch repair, is not a defining feature of the majority of adult patients with AML. Furthermore, our data does not support the hypothesis that MSI could be acquired during the progression of AML from diagnosis to relapse, as a consequence of therapeutic exposure.

Acute Disease↗

PubMed1995

Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae.

Eukaryotic genomes contain tracts of DNA in which a single base or a small number of bases are repeated (microsatellites). Mutations in the yeast DNA mismatch repair genes MSH2, PMS1, and MLH1 increase the frequency of mutations for normal DNA sequences and destabilize microsatellites. Mutations of human homologs of MSH2, PMS1, and MLH1 also cause microsatellite instability and result in certain types of cancer. We find that a mutation in the yeast gene MSH3 that does not substantially affect the rate of spontaneous mutations at several loci increases microsatellite instability about 40-fold, preferentially causing deletions. We suggest that MSH3 has different substrate specificities than the other mismatch repair proteins and that the human MSH3 homolog (MRP1) may be mutated in some tumors with microsatellite instability.

Base Sequence↗

PubMed2000

Racial disparity in the frequency of PTEN mutations, but not microsatellite instability, in advanced endometrial cancers.

Survival of African Americans with endometrial cancer is significantly worse than that of whites. Mutation of the PTEN tumor suppressor gene and microsatellite instability occur in some endometrial cancers, and they are associated with favorable prognostic features. The aim of this study was to determine whether there is a racial disparity in the frequency of these molecular alterations that contributes to differences in outcome in advanced endometrial cancer. We screened 140 stage III/IV endometrial adenocarcinomas (78 Caucasian, 62 African American) for mutations in the PTEN gene. Paired DNA samples were available in 100 cases and were analyzed for microsatellite instability using three polymorphic markers. African-American women had cancers with significantly higher stage and grade that were more often nonendometrioid. In addition, median survival of African Americans (1.0 years) was worse than that of whites (2.5 years; P = 0.02). PTEN mutation was seen in 20 of 140 (14%) cancers and was associated with endometrioid histology and more favorable survival. The frequency of PTEN mutations was significantly higher in whites (17 of 78; 22%) than in African Americans (3 of 62; 5%; P = 0.006). Microsatellite instability was found in 15% of cancers, exclusively in endometrioid cases, and was associated with favorable survival (P = 0.01). There was no racial difference in the frequency of microsatellite instability. We conclude that mutation of the PTEN tumor suppressor gene is associated with favorable survival in advanced endometrial cancer and is 4-fold more frequent in Caucasians relative to African Americans. This suggests that differences in the frequency of PTEN mutations contribute to the racial disparity in endometrial cancer survival.

Adenocarcinoma↗

PubMed2002

Helicobacter pylori impairs DNA mismatch repair in gastric epithelial cells.

BACKGROUND & AIMS: Helicobacter pylori infection is a major gastric cancer risk factor. H. pylori gastritis occurs more frequently in individuals with microsatellite instability-positive than those with microsatellite instability-negative gastric cancers, raising the possibility that H. pylori infection affects DNA mismatch repair (MMR). The aim of this study was to determine the effect of H. pylori on the expression of DNA MMR proteins and RNA in gastric epithelial cells. METHODS: Gastric cancer cell lines were cocultured with H. pylori, bacterial extracts, and Campylobacter jejuni or Escherichia coli. MutS (hMSH2 and hMSH6) and MutL (hMLH1, hPMS2, and hPMS1) DNA MMR protein and RNA levels were determined. RESULTS: All cell lines examined showed decreased levels of MutS and MutL DNA MMR proteins in a dose-dependent manner after coculture with H. pylori strains. The reduction in DNA MMR protein levels was caused by heat-sensitive H. pylori products. The levels of DNA MMR proteins were affected by C. jejuni but not by E. coli. RNA levels of hMSH2 and hMSH6 were also reduced after exposure to H. pylori. CONCLUSIONS: H. pylori infection of gastric epithelial cells leads to a decrease in DNA MMR proteins that is at least in part related to an H. pylori-induced decrease in messenger RNA levels of repair genes. These data suggest that H. pylori infection might lead to a deficiency of DNA MMR in gastric epithelial cells that may increase the risk of mutation accumulation in gastric mucosa cells and the risk of gastric cancer during chronic H. pylori infection.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Genetic alterations in head and neck cancer: interactions among environmental carcinogens, cell cycle control, and host DNA repair.

Head and neck squamous cell carcinomas (HNSCC) arise as a consequence of cumulative genetic changes brought about by continued exposure to carcinogens associated with tobacco and alcohol use, influenced by viral agents such as human papillomaviruses, in a background of acquired or heritable genetic susceptibility. The presence of widespread genomic instability in HNSCC, such as cytogenetic aberrations, allelic imbalance/loss of heterozygosity, and microsatellite instability, suggests that there is an imperfection in the host DNA repair machinery. Genomic instability with progressive accumulation of detrimental genetic alterations appears to be dependent upon a circuitous interaction between the environmental genotoxic insults and the host DNA repair machinery, the functional integrity of which is governed by the proper cell cycle control and host DNA repair capacity. Thus, it can be hypothesized that continued exposure to environmental carcinogens (ie, longstanding history of smoking and drinking), loss of proper cell cycle control (eg, inactivation of p53 or p16 tumor suppressor genes or amplification of the proto-oncongene cyclin D1), and impaired DNA repair capacity (both inherited and acquired) are prerequisites in head and neck carcinogenesis.

Alcohol Drinking↗

PubMed2003

The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation.

Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology.

Antigens, CD↗